Animal training using cognitive enhancement

ABSTRACT

Methods are disclosed to enhance the training potential of a domestic animal during training, thereby shortening the training period and/or increasing the effectiveness of the training. The method involves first administering to the domestic animal a pharmaceutical composition comprising a cognitive enhancing agent in an amount effective to improve cognitive function. The enhanced cognition allows the domestic animal to learn to perform a task and/or to change its existing behavior more effectively and on an accelerated basis. Therefore, while the animal&#39;s cognitive function is enhanced, the method then involves conditioning the domestic animal to perform a task or change an existing behavior.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.62/069,045, filed Oct. 27, 2014, which is hereby incorporated herein byreference in its entirety.

BACKGROUND

There are a variety of established methods of animal training, each withits adherents and critics. Some of the better known training proceduresinclude the Koehler method, clicker training, dominance-based training,negative reinforcement, and relationship-based training. The commoncharacteristics of successful methods are knowing the animal'sattributes and personality, accurate timing of reinforcement and/orpunishment, and consistent communication. However, each of these methodsare limited by the inherent learning potential of the animal duringconditioning.

SUMMARY

Methods are disclosed to enhance the training potential of a domesticanimal during training, thereby shortening the training period and/orincreasing the effectiveness of the training The method involves firstadministering to the domestic animal, such as a canine subject, apharmaceutical composition comprising a cognitive enhancing agent in anamount effective to improve cognitive function. While the animal'scognitive function is enhanced, the method then involves conditioningthe domestic animal to perform a task or change an existing behavior.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DETAILED DESCRIPTION

Methods are disclosed to enhance the training potential of a domesticanimal, such as a canine subject, during training By “enhance training”is meant any improvement in the speed, ease, or effectiveness oftraining. Therefore, the method can shortening the training period,increasing the effectiveness of the training, or a combination thereof.

The method involves first administering to the domestic animal apharmaceutical composition comprising a cognitive enhancing agent in anamount effective to improve cognitive function. The enhanced cognitionallows the domestic animal to learn to perform a task and/or to changeits existing behavior more effectively and on an accelerated basis.Therefore, while the animal's cognitive function is enhanced, the methodthen involves conditioning the domestic animal to perform a task orchange an existing behavior.

Cognitive Enhancing Agent

In some embodiments, the cognitive enhancing agent is any molecule,compound, or composition that is known or purported to enhance cognitivefunction in mammals. In some embodiments, the cognitive enhancing agentcomprises a psychostimulant (CNS stimulant) drug. For example, thepsychostimulant drug can be a phenethylamine derivative, which has thegeneral chemical formula:

Phenethylamine derivatives include substituted phenethylamines,substituted amphetamines, and substituted methylenedioxyphenethylamines.Non-limiting examples of phenethylamine derivatives include amphetamine,methylphenidate, dexmethylphenidate, dextroamphetamine, mixedamphetamine salts, dextromethamphetamine, lisdexamfetamine,p-methoxyamphetamine, methylenedioxyamphetamine,2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, and3,4-methylenedioxymethamphetamine, N-ethylamphetamine, fenethylline,benzphetamine, and chlorphentermine. The amphetamine can have anystereogenic configuration, including both dextro- and levo-isomers. Insome cases, the psychostimulant drug contains combinations of activeingredients and/or mixtures of stereoisomer salts. For example,Adderall® (amphetamine, dextroamphetamine mixed salts) is a mixture ofamphetamine stereoisomer salts and inactive ingredients. The activeingredients of Adderall® by salt content are 75% dextroamphetamine saltsand 25% levoamphetamine salts.

In some cases, the substituted phenethylamine comprises methylphenidate(trade names: CONCERTA, RITALIN, EQUASYM XL), which has the generalchemical formula:

Amino acid methylphenidate prodrugs may be prepared via the generalmethods described in U.S. Pat. No. 7,105,486 (which is incorporatedherein in its entirety by reference for the preparation of amphetamineamino acid prodrugs). Amino acid methylphenidate prodrugs may comprisemethylphenidate covalently bound to a single amino acid at thepiperidine nitrogen or bound to a di- or tri-peptide at this position.it is also a matter of routine organic synthesis to prepare carboxamideand carbamate methylphenidate prodrugs by reacting methylphenidate withan aliphatic aldehyde or aliphatic organic acid. Methylphenidatecontains a secondary amine group and amphetamine contains an amino groupboth of which may be reacted to form prodrugs having a chemical moietycovalently attached to the amine or amino group of the parent drugcompound. Methylphenidate possesses two centers of chirality and thuscan exist as four separate optical isomers. For example, the 2R:2′Risomer of methylphenidate is disclosed in U.S. Pat. No. 5,908,850 whichis incorporated herein in its entirety by reference.

In some cases, the phenethylamine derivatives comprises amphetamine,which has the chemical formula:

Amphetamine prodrugs, and methods of preparing amphetamine prodrugs,have been described previously. U.S. Pat. No. 7,105,486, which describesthe preparation of lisdexamfetamine, is hereby incorporated by referenceat cols. 20 to 22 for its teachings regarding the synthesis of aminoacid amphetamine prodrugs. In addition to amino acid prodrugs it ispossible to prepare a number of other amphetamine prodrugs by reactingthe amphetamine amino group with a chemically labile moiety. It iswithin the ability of those of ordinary skill in the art of chemicalsynthesis to prepare carboxamide amphetamine prodrugs by reactingamphetamine with an aliphatic aldehyde and to prepare carbamateamphetamine prodrugs by reacting amphetamine with an aliphatic organicacid. The term “lisdexamfetamine” also encompasses any pharmaceuticallyacceptable salt, polymorph or ester thereof. Lisdexamfetamine istypically administered as a dimesylate salt but includes allpharmaceutically acceptable salts of lisdexamfetamine free base.Lisdexamfetamine dimesylate (CAS Reg. No. 608137-32-3,(2S)-2,6-diamino-N-)[(1S)-1-methyl-2-phenylethyl]hexanamidedimethanesulfonate) is an amphetamine prodrug in which L-lysine iscovalently bound to d-amphetamine.

In some cases, the psychostimulant drug comprises modafinil, which hasthe chemical formula:

Modafinil can be synthesized by the method as described in U.S. Pat. No.4,927,855, which is incorporated herein by reference. In someembodiments, the psychostimulant drug comprises an acetamide derivativemodafinil, such as 2-(benzhydrylsulfinyl)acetamide. In some embodiments,modafinil polymeric forms can be used, such as those disclosed in U.S.Pat. Nos. 7,649,020; 7,405,323; 6992,219, as well as enantiomers,analogues and derivatives can be used which are disclosed in U.S. Pat.Nos. 7,704,975; 7,779,540; 7,576,133; 7,566,805; 7,541.493; 7,368,591;7,317,126; 7,316,918; 7,297.346; 7,235,691; 7,229,644; 7,141.555;7,115,281; 7,087,647; 7,057,068; 6,489,363; 6,348,500; 6,346,548;5,612,379; 5,401,776, each of which are incorporated herein in theirentirety by reference.

In some cases, the psychostimulant drug comprises amantadine (tradename: SYMMETREL), which has the following chemical formula:

Extended release forms of amantadine have been described in the art.U.S. Pat. No. 5,358,721, to Guittard et al., and U.S. Pat. No.6,217,905, to Edgren et al., which are incorporated herein in theirentirety by reference. U.S. Pat. No. 6,194,000, to Smith et al.,incorporated herein in their entirety by reference, discloses analgesicimmediate and controlled release pharmaceutical compositions utilizingNMDA receptor antagonists, such as amantadine, as the active agent. U.S.Patent Appl. Publication Nos. US 2006/0252788, US 2006/0189694, US2006/0142398, and US 2008/0227743, incorporated herein in their entiretyby reference, all to Went et al., each disclose the administration of anNMDA receptor antagonist, such as amantadine, optionally in controlledrelease form. U.S. Patent application US 2011/0189273 also incorporatedherein in its entirety by reference, discloses alternative formulationsof amantadine.

In some embodiments, the psychostimulant drug comprises a γ-aminobutyricacid (GABA) antagonists. Examples of GABA antagonists includeBicuculline and Metrazol (pentylenetetrazol), and the benzodiazepineGABA receptor antagonist Flumazenil. Thujone and muira puama may haveproperties of GABA receptor antagonism.

Pentylenetetrazol has the following chemical formula:

Several classes of compounds can modulate the pentylenetetrazoldiscriminative stimulus including 54-HTIA, 5-HT3, NMDA, glycine, andL-type calcium channel ligands.

Bicuculline is a light-sensitive competitive antagonist of GABAAreceptors. Bicuculline has the following chemical formula:

The action of bicuculline is primarily on the ionotropic GABAAreceptors, which are ligand-gated ion channels concerned chiefly withthe passing of chloride ions across the cell membrane, thus promoting aninhibitory influence on the target neuron. These receptors are the majortargets for benzodiazepines and related anxiolytic drugs.

In some embodiments, the psychostimulant drug comprises a selectiveserotonin reuptake inhibitor (SSRI). Non-limiting examples of SSRIsinclude citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,indalpine, paroxetine, sertraline, and zimelidine.

Citalopram (trade names: CELEXA, CIPRAMIL) has one stereocenter, towhich a 4-fluorophenyl group and an N,N-dimethyl-3-aminopropyl groupbind. As a result of this chirality, the molecule exists in (two)enantiomeric forms (mirror images). They are termed S-(+)-citalopram andR-(−)-citalopram. Citalopramtherefore has the following chemicalformulas:

Fluvoxamine (trade names: FLOXYFRAL, LUVOX, FEVARIN) has the followingchemical formula:

Escitalopram (trade names: LEXAPRO, CIPRALEX) has the following chemicalformula:

Paroxetine (trade name: PAXIL) has the following chemical formula:

Sertraline (trade names: ZOLOFT, LUSTRAL) has the following chemicalformula:

Fluoxetine (trade names: PROZAC, SARAFEM, LADOSE, FONTEX) has the foliochemical formula:

In some embodiments, the cognitive enhancing agent is a natural productor dietary supplement that enhances cognition, such an herb or plantextract. However, in some embodiments, the disclosed methods include atleast one cognitive enhancing agent that is not a natural product ordietary supplement.

For example, green tea and other natural and synthetic sources ofcatechins, and bioflavanoids, flavanols, flavandiols, flavanoids, andtannins or derivatives thereof, can enhance cognitive ability.

Caffeine, when consumed in conjunction with L-theanine, a common aminoacid found in green tea, creates more long-lasting and beneficialeffects, including a boost to working memory, rapid visual informationprocessing, and especially attention switching (i.e. reduceddistractibility). The reason this works is that the L-theanine, whichcan cross the blood-brain barrier, counteracts the negative stimulanteffects of caffeine, including anxiety and increased blood pressure.

Creatine has also been shown to improve memory and attention span. Itplays a pivotal role in brain energy homeostasis, acting as a buffer forcytosolic and mitochondrial pools of cellular energy.

Piracetam, also known as Nootropyl or Lucetam, works by improving thefunctioning of (ACh) transmitters and receptors. This can be ingestedwith choline to experience its benefits, including increased mentalclarity, spatial memory, and an overall boost in brain functioning.

Found primarily in northern India, Bacopa monnieri is a perennialcreeping herb that's been used for centuries to enhance memory,learning, and overall cognitive performance (in addition to its use asan anti-inflammatory, analgesic, antipyretic, and sedative). The activeingredients responsible for these effects include sulfhydryl andpolyphenol, compounds that lessen oxidative stress.

Ginkgo Biloba extract comes from maidenhair, an extremely unique treenative to China that has no relatives—what is considered a livingfossil. Extracts of Ginkgo leaves contain flavonoid glycosides andterpenoids (ginkgolides, bilobalides) which are renowned for theirpharmacological benefits, including their ability to improve memory andconcentration.

Asian ginseng can be used to improve working memory, attention,calmness, mood, and even reduce fatigue.

Rhodiola rosea has an affect on serotonin and dopamine levels due tomonoamine oxidase inhibition. Rhodiola rosea can improve cerebralfunctions (such as associative thinking, short-term memory, calculation,ability of concentration, and speed of audio-visual perception).

Found in Spain and southern France, Salvia lavandulaefolia is anaromatic herb that boosts acetylcholine function. Studies have shownthat it can enhance memory.

Veterinary Pharmaceutical Formulation

Disclosed are veterinary pharmaceutical formulations containingtherapeutically effective amounts of one or more of the disclosedcognitive enhancing agents and a pharmaceutically acceptable carrier.Pharmaceutical carriers suitable for veterinary administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. For example, physiologically acceptable formulationexcipients are described in “Gennaro, Remington: The Science andPractice of Pharmacy” (20th Edition, 2000), which is incorporated byreference herein. All ingredients, carriers and excipients may besubstantially pharmaceutically or veterinary pure and non-toxic in theamounts employed and may be compatible with the pharmaceutically activeingredients.

The formulations can be administered directly or in the form of suitablepreparations, enterally, parenterally or dermally. Enteraladministration of the formulations takes place, for example, orally inthe form of powder, tablets, capsules, pastes, potions, granules, orallyadministered solutions, suspensions and emulsions, boli, medicated feedor drinking water.

Suitable preparations include oral solutions and concentrates for oraladministration after dilution; emulsions and suspension for oraladministration; and semisolid preparations; formulations in which theactive compound is processed in an ointment base or in an oil-in-wateror water-in-oil emulsion base; solid preparations, such as powders,premixes or concentrates, granules, pellets, tablets, caplets, boli andcapsules, with tablets the preferred form; and oral solutions preparedby dissolving the active compound in a suitable solvent and, ifappropriate, adding additives such as solubilizers, acids, bases, buffersalts, antioxidants and preservatives. Suitable solvents may includephysiologically acceptable solvents, such as water, alcohols, such asethanol, butanol, benzyl alcohol, glycerol, propylene glycol andpolyethylene glycol, N-methylpyrrolidone, and mixtures of the same. Theactive compounds can, if appropriate, also be dissolved inphysiologically acceptable vegetable or synthetic oils. Solubilizers mayinclude solvents which promote dissolution of the active compound in themain solvent or substances which prevent precipitation of the activecompound. Examples are polyvinyl pyrrolidone, polyoxyethylated castoroil and polyoxyethylated sorbitan esters.

By mixing an active ingredient with a carrier in the liquid phase, theactive can become “encapsulated” or substantially covered in a matrix ofcarrier after the spray granulation process. Granulation is generallyperformed by spraying liquid into the fluidized powder. The granules cansubsequently be dried with heated air.

Suitable excipients may include physiologically acceptable inert solidssuch as, for example, sodium chloride, calcium carbonate, hydrogencarbonates, aluminum oxides, silicas, clays, precipitated or colloidalsilicon dioxide and phosphates. Additional excipients that can bepresent in the formulation include fillers, antioxidants, colorants,flavors, sugar components, surfactants, stabilizers, flow agents,disintegration agents, preservatives, and/or lubricating agents.Additional suitable auxiliaries can include lubricants, such as, forexample, magnesium stearate, stearic acid, talcum and bentonites,disintegration-promoting substances, such as starch or transverselycrosslinked polyvinyl pyrrolidone, binders, such as, for example,starch, gelatin or linear polyvinyl pyrrolidone, and dry binders, suchas microcrystalline cellulose. Other suitable excipients include sugar,cellulose, carboxymethyl cellulose, Aerosil, nutrients and feedstuffs,such as milk powder and pork liver powder, animal meals, ground andcrushed cereal meals, Avicel PH102, and starches.

In some embodiments, the solid oral dosage form is a soft chew. In softchew formulations the forming agent is important for the texture of thesoft chew and the possibility to form single soft chews from the doughthat stay intact and separate. Forming agents are agents providingtexture to the soft chew product, like for example polyethylene glycol(PEG), microcrystalline wax, cetyl alcohol or polyvinylpyrrolidone(PVP). In an embodiment, the forming agent is polyethylene glycol (PEG).Moreover, depending upon the desired consistency of the soft chew,different molecular weight PEG may be utilized. In an embodiment, PEG8000 is utilized. However, the PEG chosen is a matter of choice and themolecular weight may be higher or lower than 8000, but preferably higherthan 600. Alternatively PEG 3500 might be used.

The materials in the final formulation, such as the excipients,auxiliaries, synergists and other materials, which aid in delivery,shelf-life, desired physical structure and so forth will be referred toherein generally as carrier material. As stated herein, carrier materialcould be pharmaceutically active under certain circumstances.

The disclosed pharmaceutical composition can be administered in anamount effective to enhance the canine subject's cognitive abilityduring the training period. Therefore, the effective dosage can beempirically determined based on the specific drug and route ofadministration.

In one embodiment, cognitive enhancing agent is administered in a doseequivalent to parenteral administration of about 0.1 ng to about 100 gper kg of body weight, about 10 ng to about 50 g per kg of body weight,about 100 ng to about 1 g per kg of body weight, from about lug to about100 mg per kg of body weight, from about 1 μg to about 50 mg per kg ofbody weight; and from about 100 μg to about 500 μg to per kg of bodyweight. Alternatively, the amount of cognitive enhancing agentadministered to achieve a therapeutic effective dose is about 0.1 ng, 1ng, 10 ng, 100 ng, 1 μg, 10 μg, 100 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90mg, 100 mg, 500 mg per kg of body weight or greater.

In some embodiments, the pharmaceutical composition is administered atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, or 24 hours prior to a conditioning activity. Thetraining period can last from 1 day to several weeks or more. Therefore,the pharmaceutical composition can be administered every 1, 2, 3, 4, 5,6, 7, days or more, during the training period. In some cases,administration of the pharmaceutical composition is continued at least1, 2, 3, 4, 5, 6, 7, or more days after training has completed.

Domestic Animals

The disclosed methods may in some embodiments be used to enhance thetraining of any domestic mammal Non-limiting examples of domesticmammals include dogs (Canis lupus familiaris), cat (Felis silvestriscatus), ferret (Mustela putorius furo), sheep (Ovaris aries), pig (Susscrofa domesticus), goat (Capra aegagrus hircus), horse (Equus feruscaballus), or cattle (Bos primigenius Taurus). The animal can be acompanion animal, such as a dog, cat, or ferret. The animal can also bea circus animal, such as an elephant, lion, tiger, or non-human primate,or a marine mammal, such as a seal, whale, dolphin, otter, or walruses.

In particular embodiments, the disclosed methods is used to enhancetraining of a canine animal of the species Canis lupus familiaris(a.k.a, domestic dog). For example, the American Kennel Club (AKC)recognizes 152 breeds of dog distributed in seven breed groups (Herding,Hound, Nonsporting, Sporting, Terrier, Toy, and Working). Non-limitingexamples of dog breeds whose training can be enhanced with the disclosedmethods include, but are not limited to, Afghan Hound, Airedale Terrier,Akita, Alaskan Malamute, American Eskimo Dog, American Foxhound,American Hairless Rat Terrier, American Staffordshire Terrier, AmericanWater Spaniel, Australian Cattle Dog, Australian Shepherd, AustralianTerrier, Basenji, Basset Hound, Beagle, Bearded Collie, BedlingtonTerrier, Belgian Laekenois, Belgian Malinois, Belgian Sheepdog, BelgianTervuren, Bernese Mountain Dog, Bichon Frise, Bloodhound, Border Collie,Border Terrier, Borzoi, Boston Terrier, Bouvier des Flandres, BoykinSpaniel, Boxer, Briard, Brittany, Bulldog, Brussels Griffon,Bullmastiff, Bull Terrier, Cairn Terrier, Cardigan Welsh Corgi, CavalierKing Charles Spaniel, Chesapeake Bay Retriever, Chihuahua, ChineseCrested, Chinese Shar-Pei, Chow Chow, Clumber Spaniel, Cocker Spaniel,Collie, Curly-Coated Retriever, Dachshund, Dalmatian, Dandie DinmontTerrier, Doberman Pinscher, Dogo Canario, English Cocker Spaniel,English Foxhound, English Setter, English Springer Spaniel, EntlebucherMountain Dog, Field Spaniel, Flat-Coated Retriever, French Bulldog,German Longhaired Pointer, German Shepherd Dog, German ShorthairedPointer, German Wirehaired Pointer, Giant Schnauzer, Golden Retriever,Gordon Setter, Great Dane, Great Pyrenees, Greater Swiss Mountain Dog,Greyhound, Harrier, Havanese, Ibizan Hound, Irish Setter, Irish Terrier,Irish Water Spaniel, Irish Wolfhound, Italian Greyhound, Jack RussellTerrier, Keeshond, Kerry Blue Terrier, Komondor, Kuvasz, LabradorRetriever, Leonberger, Lhasa Apso, Lowchen, Maltese, ManchesterTerrier—Standard, Manchester Terrier—Toy, Mastiff, Miniature BullTerrier, Miniature Pinscher, Miniature Poodle, Miniature Schnauzer,Munsterlander, Neapolitan Mastiff, Newfoundland, New Guinea Singing Dog,Norwegian Elkhound, Norwich Terrier, Old English Sheepdog, Papillon,Pekingese, Pembroke Welsh Corgi, Petit Basset Griffon Vendeen, PharaohHound, Pointer, Polish Lowland Sheepdog, Pomeranian, Portuguese WaterDog, Presa Canario, Pug, Puli, Pumi, Rhodesian Ridgeback, Rottweiler,Saint Bernard, Saluki, Samoyed, Schipperke, Scottish Deerhound, ScottishTerrier, Silky Terrier, Shetland Sheepdog, Shiba Inu, Shih Tzu, SiberianHusky, Smooth Fox Terrier, Soft Coated Wheaten Terrier, SpinoneItaliano, Staffordshire Bull Terrier, Standard Poodle, StandardSchnauzer, Sussex Spaniel, Tibetan Spaniel, Tibetan Terrier, Toy FoxTerrier, Toy Poodle, Vizsla, Weimaraner, Welsh Springer Spaniel, WelshTerrier, West Highland White Terrier, Wirehaired Pointing Griffon,Whippet, Yorkshire Terrier.

The methods can be used for animals of any age or health. For example,in some cases, the animal is a juvenile dog, an adolescent dog, an adultdog, or a senior dog. Therefore, the animal can be a canine subject fromtwo to six months in age, from six to eighteen months in age, fromtwelve months to three years in age, or from six to ten years in age.

In some embodiments, the animal is a healthy animal, such as an animalthat has not been diagnosed with a cognitive deficit or any otherneurological disease.

Canine Conditioning

The disclosed methods can be used with any forms of conditioningsuitable to train domestic animals. For example, conditioning caninvolve training the animal for a task selected from the groupconsisting of agility, hunting, herding, tracking, detection,assistance, search and rescue, and guarding. The disclosed method canalso be used to train domestic animals to refrain from unwantedbehavior. For example, the method can involve housebreaking the domesticanimal. Animal training can involve socialization of the domesticenvironment, basic obedience training, or training for specializedactivities including law enforcement, search and rescue, hunting,working with livestock, assistance to people with disabilities,entertainment, dog sports, detection and protecting people or property.

The disclosed methods can be used with obedience training, to trainservice animals (e.g., Seeing Eye dogs, health assistance dogs, andcompanion dogs), to train military and police dogs (e.g., to detectdrugs and/or explosives, apprehend subjects, and guard people orlocations), or to train animals to perform tricks.

There are a variety of established methods of animals training that canbe used with the disclosed methods, each with its adherents and critics.Some of the better known training procedures include the Koehler method,clicker training, dominance-based training, negative reinforcement andrelationship-based training. The common characteristics of successfulmethods are knowing the animal's attributes and personality, accuratetiming of reinforcement and/or punishment and consistent communication.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method for enhancing housebreaking of ajuvenile canine subject, comprising (a) administering to the juvenilecanine subject a pharmaceutical composition comprising a cognitiveenhancing substituted phenethylamine in an amount effective to improvecognitive function; and (b) housebreaking the canine subject.
 2. Themethod of claim 1, wherein the substituted phenethylamine is selectedfrom the group consisting of amphetamine, methylphenidate,dexmethylphenidate, dextroamphetamine, mixed amphetamine salts,dextromethamphetamine, and lisdexamfetamine.
 3. The method of claim 1,wherein the canine subject is from two to six months in age.
 4. Themethod of claim 1, wherein the pharmaceutical composition isadministered at least daily over a period of 1 to 90 days.
 5. The methodof claim 1, wherein the pharmaceutical composition is administered as acontrolled release formulation that provides an effective dose over aperiod of 1 to 90 days.
 6. The method of claim 1, wherein thepharmaceutical composition is administered at least one hour beforeconditioning.
 7. The method of claim 6, wherein the pharmaceuticalcomposition is administered from 1 to 24 hours before conditioning. 8.The method of claim 1, wherein the pharmaceutical composition isadministered during conditioning and for at least one day afterconditioning.
 9. The method of claim 1, wherein the canine subject hasnot been diagnosed with a cognitive deficit.